New pyridine compounds



a l a United States Patent F NEW PYRIDINE COMPOUNDS Milton Joel Allen and William Laszlo Bencze, Summit,

N.J., assignors to Ciba Pharmaceutical Products, Inc., Summit, N.J., a corporation of New Jersey No Drawing. Filed Feb. 24, 1959, Ser. No. 794,858

12 Claims. (Cl. 260-296) This invention relates to a new series of pyridine comin which each of the radicals R and R stands for 3- pyridyl or 4-pyridyl radicals, and each of the radicals R and R for a lower hydrocarbon radical, salts and quaternary ammonium compounds thereof, and mixtures of these compounds, as well as process for the preparation of these compounds.

The 3-pyrid'yl or 4-pyridyl radicals may be unsubstituted or may contain, for example, lower alkyl radicals, e.g. methyl or ethyl.

The lower hydrocarbon radicals, representing R and R are preferably lower alkyl radicals, for example, methyl, ethyl, propyl or isopropyl.

Salts of the alcohols of this invention are therapeutically acceptable acid addition salts with inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; thiocyanic acid; sulfuric or phosphoric acids; or with organic acids, such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, ascorbic, benzoic, phenylacetic, p-aminobenzoic, p-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicyclic, p-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, methane sulfonic, ethane sulfonic, hydroxyethane sulfonic, benzene sulfonic, p-toluene sulfonic, naphthalene sulfonic or sulfanilic acid or methionine, tryptophane, lysine or arginine. Monoor, preferably, bis-salts may be obtained.

Quaternary ammonium compounds are those with reactive esters formed by alcohols, especially lower alkanols, and strong inorganic or organic acids. Such esters are particularly lower alkyl halides, e.g. methyl iodide, methyl bromide, methyl chloride, ethyl chloride, propyl chloride or isopropyl chloride; di-lower alkyl sulfates, e.g. dimethyl or diethyl sulfate; or lower alkyl aryl sulfonates, e.g. methyl toluene sulfonate. Depending on the conditions used in the procedure of formation, the monoor the bis-quaternary ammonium compounds may be obtained.

It has been found that the new pyridine compounds of 2 2,966,494 Patented Dec. 27, 1960 ice Many diseases known to be directly influenced by a hyperactivity of this vital gland, such as the Cushings Syndrome or the adrenogenital Syndrome are difficult to treat, because the adrenal cortex does not rely on an outside source for the preparation of the steroidal compounds and can therefore not be regulated by dietary measures. Until now only few compounds are known to have any slowdown effect on the activity of the adrenal cortex; none of them has proven to be satisfactory due to low activity and/or unfavorable therapeutic ratio between activity and toxicity, as well as undesirable side effects.

The new compounds of this invention have been found to exert a remarkable and prolonged suppression of the activity of the adrenal cortex and thus the production of adrenocortical hormones, such as derivatives of 174xhydroxy-pregnane, e.g. cortisone, without showing adverse secondary or essentially toxic effects. Therefore, the new compounds may be used, as mentioned before, to treat conditions related to the hyperactivity of the adrenal cortex, such as the Cushings Syndrome or the adrenogenital Syndrome! Furthermore, they may be used to influence diseases to which the adrenal cortex may contribute with undesirable salt and water retention, such as, for example, in cardiac failure, liver disease with ascites, nephrotic Syndrome or toxemia of pregnancy.

Furthermore, it has been found that the new pyridine derivatives cause a hypersensitivity to insuline, which is manifested by a depression of the blood sugar level and an increase of liver glycogen. They may therefore also be used as hypoglycemic agents in hyperglycemia.

Especially valuable with respect to adrenal cortex inhibitory activity are the pyridine derivatives of the formulae:

CH8 N zi-tf CH-OH as well as the salts, for example, the dihydrochlorides thereof.

The new pyridine compounds, especially those specifically mentioned above, are capable of reversing experimentally induced ascites in the dog in a dose of from about 1 to mL/kg. (parenterally), which results in an increased output of urine and sodium. Also, the new pyridine derivatives may be used as diagnostic tools to define the pathogenic role of aldosterone in patients exhibiting sodium retention associated with increased urinary excretion of the steroid, and thus aid in predicting the results of adrenal surgery.

The new compounds may be used in the form of pharmaceutical preparations, which contain the new pyridine derivatives, salts or quaternary ammonium compounds thereof or mixtures of such compounds in admixture with pharmaceutical organic or inorganic, solid or liquid carriers suitable for enteral, e.g. oral, or parenteral administration. For making up the preparations there may be employed substances which do not react with the new compounds, such as, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as tablets, dragees or capsules, or in liquid form, for example, as solutions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, salts for varying the osmotic pressure or buffers such as sodium metaphosphate. They may also contain, in combination, other therapeutically useful substances.

The new compounds of this invention having the formulae:

I'M R|CH(IIR= E R4 and 1,3: RiCR2 CH-OH in which R R R and R have the above-given meaning, the salts or quaternary ammonium compounds thereof may be prepared from the corresponding ketones of the formulae:

in which R R R and R have the above-given'meaning, salts or mixtures thereof, by reduction, and, if desired, converting any resulting salt into the free base, and/or converting any free base obtained into a salt or a quaternary ammonium compound thereof, and/or, if desired, separating any resulting mixture into the single compounds.

The reduction may be carried out with hydrogen in the presence of a catalyst containing a metal of the eighth group of the periodic system such as palladium, e.g. palladium on charcoal; care has to be taken that the pyridine derivatives are not reduced to the corresponding piperidine compounds. The reducing reagents of choice are aluminum hydrides, such as, for example, alkali metal aluminum hydrides, e.g. lithium aluminum hydride; or borohydrides, such as, for example, alkali metal borohydrides, e.g. sodium borohydride, which reagents may be used in the presence of a solvent, such as an ether, e.g. diethylether or tetrahydrofurane, a lower alkanol, e.g. methanol or ethanol, water or mixtures of such solvents, depending on the type of reagent employed. The reaction is carried out, if desired, at an elevated temperature, for example, at the boiling temperature of the solvent.

The starting material used in the above-described reaction may be prepared by rearranging diols of. the formula:

Ra Rt R1---R1 in which R R R and R have the above-given meaning, or salts thereof, in the presence of a strong Lewis acid. Salts of the diols used as the starting materials are especially those with inorganic acids, such as, the dihydrohalides, e.g. dihydrochlorides or dihydrobromides, or the disulfates. If the free compound is used in the rearrangement step the salt may be formed under the acidic conditions of the reaction.

Strong Lewis acids capable of bringing about the pinacolone rearrangement of the diols or the. saltsthere- 4 of, are especially strong inorganic acids, particularly sulfuric acid; other acids, such as hydrochloric or perchloric acids, give less favorable results due to the formation of by-products. The acidic reagents are preferably used in the concentrated form; concentrated sulfuric acid is the reagent of choice. The rearrangement is preferably carried out by heating the reaction mixture from about 50 to about 200; temperatures below 50 slow down the rate of the reaction considerably and those higher than 200 increase the formation of byproducts. Instead of carrying out the reaction at atmospheric pressure, a closed vessel may be utilized to provide increased pressure. To avoid contact with atmospheric oxygen the reaction may be performed in the presence of an inert gas, e.g. nitrogen.

Under the ordinary reaction conditions a mixture of both ketones may be obtained having the formulae:

a R C( R, l1.

Conjugated Ketone (I) and R: R,d7-R,

Unconjugated Ketone (II) The proportions in which the two types are formed depend on the starting material used, i.e. on the position with which the pyridine radical is attached to the diol portion, and/or on the reaction conditions. Thus, for example, the 2,3-bis-(3-pyridyl)-butane-2,3-diol and the 2,3-bis-(4-pyridyl)-butane-2,3-diol yield mixtures containing the corresponding conjugated (I) and unconjugated (II) ketones in a ratio of about 3:1, when treated with sulfuric acid. In addition to the desired pinacolone rearrangement products, the ketones, certain byproducts may be obtained, the formation of which depends again on the choice of starting material and the reagent used. For example, a byproduct, which is obtained in the rearrangement of the 2,3-bis-(4-pyridyl)-butane-2,3-diol is the 2,3-bis-(4-pyridyl)-butadiene, which may be formed by double dehydration.

The mixture of the two ketones I and II may be separated, if desired, into the two constituents by fractional crystallization, which may also be carried out after the conversion of themixture of free bases into the mixture of the salts thereof or into the mixture of the functional ketone derivatives, e.g. the oximes, thereof. After separation into the single compounds by fractional recrystallization these may be easily reconverted into the free bases; the salts by treatment with an alkaline reagent, e.g. aqueous sodium hydroxide or aqueous ammonia, the functional ketone derivatives by acidic hydrolysis, e.g. with aqueous sulfuric acid, and, if desired, by subsequent treatment with a base. The mixtures of the free bases may also be separated by fractional distillation; however, the separation may not be complete, if the boiling points ofthe two constituents do not differ greatly. A further method of separation comprises adsorbing the mixture on an adsorbent and eluting the constituents of the mixture. A preferred procedure is chromatography, in which the mixture is adsorbed on aluminum oxide, having preferably basic properties. Aluminum oxide may be replaced by a cation exchanger, such as a sulfonated polystyrene exchanger (Dowex 50), as an adsorbent. The eluating solvents are chosen according to the relative polarity of the different constituents of the mixture.

The diols of the formula:

I ar

in which R R R and R have the above-given meaning as well as the salts thereof, which are used for the preparation of the starting materials, are know [Allen, J. Org- Chem, vol. 15, p. 436 (1950)] or, if new, may be prepared according to the method used for the preparation of the known compounds.

The new compounds of this invention may be obtained in the form of the free bases or as the salts thereof. A salt may be converted into the free base by customary procedure, for example, by reaction with an aqueous alkaline reagent, such as an alkali metal hydroxide, e.g. lithium sodium or potassium hydroxide; an alkali metal carbonate, e.g. sodium carbonate or potassium hydrogen carbonate; or ammonia. A free base may be transformed into its therapeutically useful acid addition salts by reaction with appropriate inorganic or organic acids, such as those outlined above, for example, in the presence of a lower alkanol, e.g. methanol, ethanol, propanol or isopropanol; or an ether, e.g. diethylether, or a mixture of such solvents. Depending on the conditions used monoor bis-salts may be obtained.

The new pyridine derivatives of this invention may be converted into the quaternary ammonium compounds by reacting the tertiary bases with an ester formed by a hydroxylated lower hydrocarbon compound and a strong inorganic or organic acid. Hydroxylated lower hydrocarbon compounds contain from 1 to 7 carbon atoms, and the esters thereof are more especially those with mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, or sulfuric acid. Such esters are specifically lower alkyl halides, e.g. methyl iodide, methyl bromide, methyl chloride, ethyl bromide or propyl chloride; di-lower alkyl sulfates, e.g. dimethyl or diethyl sulfate; or lower alkyl aryl sulfonates, e.g. methyl p-toluene sulfonate. The quaternizing reactions, such as outlined above, are performed in the presence or absence of a solvent, at room temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure. Suitable solvents are more especially lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol; lower alkanones, e.g. acetone or methyl ethyl ketone; or organic acid amides, e.g. formamide or dimethylformamide.

A quaternary ammonium compound may be converted into the corresponding quaternary ammonium hydroxide, for example, by reacting a resulting quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, or by treating a quaternary ammonium salt with an anion exchanger or by electrodialysis. From the resulting base there may beformed quaternary ammonium salts by reaction with the. acids, such as the inorganic and organic acids outlined hereinbefore for the formation of acid addition salts; or with mono-lower alkyl sulfates such as methyl or ethyl sulfate. A resulting quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without conversion into the quaternary ammonium hydroxide; for examp e, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or the quarternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol.

The invention also comprises any modification of the general process wherein a compound obtainable as an intermediate at any stage of the process is used as start ing material and the remaining step(s) of the process is(are) carried out, as well, as any new intermediates.

This is a continuation-in-part application of our application Serial No. 720,053, filed March 10, 1958, which in turn is a continuation-in-part application of our applications Serial No. 661,620, filed May 27, 1957 (now abandoned) and Serial No. 688,845, filed October 8, 1957 (now abandoned).

The following examples illustrate the invention. They are not to be construed as being limitations thereon. "Temperatures are given in degrees centigrade.

Example 1 A solution of 6.42 g. of Z-methyl-l,2-bis-(3-pyridyl)= propane-l-onein 25 ml. of ether is slowly added to a boiling suspension of 1.08 g. of lithium aluminum hydride in 50 ml. of ether, and the mixture is refluxed for 8 hours. The excess of lithium aluminum hydride is carefully destroyed with water and a 6 N aqueous solution of hydrogen chloride is added to dissolve the precipitate. The aqueous solution is adjusted to pH 8 with a 2 N aqueous solution of sodium hydroxide and then twice extracted with ethyl acetate; the latter solution is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The organic solvent is evaporated and 6.0 g. of the remaining viscous oil is distilled, B.P. -150/ 0.05 mm. Upon standing, the oil crystallizes and is recrystallized from a mixture of ethyl acetate and pentane to yield the 2-methyl-l,2-bis- (3-pyridyl) -propane-1-ol of the formula:

N N Q (I)H JHa By treating 6.1 g. of 3,3-bis-(3-pyridyl)-butane-2-one with 2.0 g. of lithium aluminum hydride as described hereinabove, 5.7 g. of crystalline material is obtained from the ethyl acetate extraction which after crystalliza tion from a mixture of ethanol, ether and pentane, and subsequent distillation yields the 3,3-bis-(3-pyridyl)-' butane-Z-ol of the formula:

on-on B.P. /01 mm., which melts at 165l66. i

The 2-methyl-1,2-bis-(3-pyridyl)-propane-1-ol is converted to the dihydrobromide by dissolving the base in concentrated aqueous hydrobromic acid, evaporating the water and recrystallizing the residual salt from a mixture of ethanol and ether.

A mixture of 2-methyl-l,2-bis-(3-pyridyl)-propane-1-ol and methyl iodide in 95 percent ethanol is refluxed and the reaction mixture concentrated to give the dimethiodide of Z-methyl-1,2-bis-(3-pyridyl)-propane-1-ol, which is recrystallized from ethanol.

The starting material used in the reduction procedure may be prepared as follows: A solution of 1430 g. of 3-acetylpyridine in 7042 ml. of a l N aqueous solution of potassium hydroxide is placed into the cathode chamber containing a mercury cathode with a surface of 353 cm. and is separated from the anode chamber by an Alundum membrane. As anode a platinum wire is used and the anolyte consists of a 1 N solution of aqueous potassium hydroxide which is replenished from time to time. The electrolysis is carried out at a reference potential of -2.4 volts v. a standard calomel electrode. An initial current density of 0.0403 ampere/cm. is obtained which drops to 0.0195 ampere/cm. at the end of the reduction, which is carried on over a period of 1682 minutes at 15-20". The catholyte is filtered, the solid material is washed with water and dried. 430 g. of the 2,3- ois-(S-pyridyl)-butane-2,3-diol is recrystallized from water, M.P. 244245.

A total amount of 300 g. of 2,3-bis-(3-pyridyl)-2,3- butanediol is added in 10 to 20 g. portions to 1000 ml. of concentrated sulfuric acid while stirring. During the addition the temperature is kept at 50-60 and is subsequently raised to 75, at which temperature it is maintained for 7 hours. The mixture is then allowed to stand 'at room temperature for 12 hours, and is poured on ice.

.The pH is brought to about 8 by addition of a 50% aq us so ut o Q sqd l m h dr d t mP m assault kept below 50. The aqueous solution is extracted twice with ether and the ether solution is washed twice with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, and the ether evaporated to dryness under reduced pressure. 175 g. of the resulting residue is dissolved in a mixture of 50 ml. of ether and 50 ml. of pentane and cooled in the refrigerator. By keeping the solution in the cool over night, 72 g. of the Z-methyl- 1,2-bis-(3-pyridyl)propane-bone is obtained and is recrystallized from a lzl-mixture of ether and pentane.

The mother liquor obtained from the crystallization step of the crude product with a mixture of ether and pentane contains, according to the infrared spectrum, an about lzl-mixture of the two ketone compounds and is worked up as follows: The solvents are distilled 01f and 45.4 g. of the resulting residue is dissolved in ethanol. A solution of 85 g. of hydroxylamine sulfate in 100 ml. of water, then a mixture of 80 g. of sodium acetate and 20 g. of sodium carbonate in 200 ml. of water are added in succession. After refluxing for hours the ethanol is removed under reduced pressure and the pH adjusted to 8 by adding an aqueous solution of potassium carbonate. The aqueous solution is extracted three times with ethyl acetate, however part of the solid material cannot be dissolved and is filtered off. The ethyl acetate solution is dried over sodium sulfate and the solvent partially evaporated. The resulting precipitate is filtered off, and ether is added to the filtrate, whereupon 16 g. of a crystalline material is formed which is filtered off, and the filtrate is evaporated to dryness. The remaining viscous oil is dissolved in ethyl acetate, ether is added and 5.5 g. of crystalline material precipitates which melts at 132-137", and is redissolved in 70 ml. of ethyl acetate. The insoluble material is filtered off and the filtrate cooled to 8. 4.2 of the oxime of 3,3-bis-(3-pyridyl)-butane- 2-one precipitates, melting at l32-134.

1 g. of the oxime of 3,3-bis-(3-pyridyl)-butane-2-one is refluxed for 6 hours in 20 ml. of a 2 N aqueous solution of sulfuric acid and allowed to stand at room temperature over night. The solution is made basic to pH 8 with a 10% aqueous solution of sodium hydroxide, then extracted three times with ether, which solution is then washed with a saturated aqueous solution of sodium chloride and dried over sodium carbonate. The ether is evaporated leaving 0.9 g. of a viscous oil, which does not respond to crystallization upon seeding with crystalline-2- methyl-l,2-bis-(3-pyridyl)propane-Lone previously obtained. It is distilled, B.P. 130-135/ 0.05 mm., and the distillation is stopped after one third of the original amount is collected.

The distillate is dissolved in a lzl-mixture of water and concentrated hydrobromic acid, the water is evaporated under reduced pressure and the residue is triturated with a mixture of methanol and ether; the crystalline material is filtered off and recrystallized from the same mixture. The resulting dihydrobromide of the 3,3-bis-(3- pyridyl)-butane-2-one melts at 240-243 and gives a melting point depression with a sample of the dihydrobromide of Z-methyl-1,2-bis-(3-pyridyl)-propane-l-one to be described hereinafter.

A solution of the dihydrobromide of 3,3-bis-(3- pyridyl)-butane-2-one in water is adjusted to pH 8 with a 2 N aqueous solution of sodium hydroxide, the solution extracted with ethyl acetate which solution is dried and then evaporated. The residue is chilled to 80 in a mixture of ether and pentane, to yield the 3,3-bis- (3-pyridyl)-butane-2-one, M.P. 47-49". A mixture with 2-methyl-1,2-bis- S-pyridyD-propane-Z-ohe previously obtained melts at room temperature.

The lzl-mixture of the two ketones one of which contains a conjugated carbonyl group, the other an unconjugated carbonyl group, obtained after the crystallization of the reaction mixture from ether and pentane, may also be separated into the two constituents as follows: 5.7 g. of said mixture in 10 ml. of benzene is placed on a Gil column containing 250 g. of aluminum oxide (basic, activity III) which has been washed with hexane. The lzl-mixture fraction of hexane and benzene and the henzene fraction contain a total of 1.64 g. of crystalline 2- methyl-l,2-bis-(3-pyridyl)-propane-1-one, the ether fraction 2.10 g. of the oily 3,3-bis-(3-pyridyl)-butane -2-one.

Example 2 The 2-methyl-1,2-bis-(4-pyridyl)-propane-1-ol and the 3,3-bis-(4-pyridyl)-butane-2-ol may be obtained by treating the 2-methyl-1,2-bis-(4-pyridyl)-propane-1 one and the 3,3-bis-(4-pyridyl)-butane-2-one, respectively, with lithium aluminum hydride according to the method described in Example 1.

The starting material used in this reaction may be prepared according to the procedure given in Example 1: 4-' acetyl-pyridine is electrolytically reduced, using as a catholyte a solution of g. of the 4-acetyl-pyridine in 460 ml. of a 1 N aqueous solution of potassium hydroxide; the resulting 2,3-bis-(4-pyridyl)-butane-2,3-diol (99 g.) is recrystallized from a mixture of ethyl acetate and methanol, M.P. 219-220.

A solution of 5 g. of 2,3-bis-(4-pyridyl)-butane-2,3- diol in 30 ml. of concentrated sulfuric acid is allowed to stand at 60-66 for 14 hours and at room temperature for an additional 8 hours and is then poured on ice. The aqueous mixture is rendered basic to pH 8 with a 50% aqueous solution of sodium hydroxide and extracted three times with ethyl acetate. The organic solution is washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate and then concentrated to about 10 ml. under reduced pressure. Some unreacted starting material which precipitates is filtered off and the filtrate evaporated to dryness. After trituration with ether the crystalline material is collected and recrystallized from a mixture of ethanol, ether and pentane to yield the 2,3-bis-(4-pyridyl)-butadiene, M.P. 133-135 The filtrate obtained after trituration with ether is evaporated to dryness and the oily residue distilled to yield 1.05 g. of an oil. Infrared studies show that a mixture of an unconjugated and a conjugated ketone is obtained, which is redistilled, B.P. 122-126/ 0.1 mm. 0.650 of the distillate is crystallized from a mixture of ethanol, ether and pentane and a solid material is obtained, which is recrystallized from a mixture of ether and pentane; the 2 methyl 1,2 bis (4 -pyridyl) propane l one is obtained in colorless needles, M.P. 75-76".

The mothers liquor obtained from the crystallization of the distillate is evaporated to dryness and the crystal line residue is chromatographed on an aluminum oxide column (neutral, activity III). An additional amount of 2-methyl-1,2-(4-pyridyl)-propane-1-one is eluated with a mixture of benzene and hexane and with benzene; the 3,3-bis-(4-pyridyl)-butane-2-one is eluated with ether and is recrystallized from a mixture of ether and pentane, M.P. 73-74".

Example 3 By treating the mixture of 2-ethyl-l,2-bis-(3-pyridyl)- butane-l-one and 4,4-bis-(3-pyridyl)-hexane-3-one with lithium aluminum hydride according to the procedure described in Example 1, the mixture of 2-ethyl-1,2-bis- (3 pyridyl) butane 1,2 bis (3 pyridyl) butane- 1-ol and 4,4-bis-(3-pyridyl)-hexane-3-ol can be obtained.

The starting material used in this reaction may be prepared according to the procedure described in Example 1: A solution of 6 g. of 3-propionyl-pyridine in 7.5 ml. of ethanol and 22.5 ml. of 1.5 N aqueous potassium hydroxide is electrolytically reduced; the 3,4- bis-(S-pyridyl)-hexane-3,4-diol melts at 188-189.

A mixture of 2 g. of 3,4-bis-(S-pyridyl)-hexane-3,4-diol in 10 ml. of concentrated sulfuric acid is kept at room temperature for 20 hours and then poured on ice. The pH of the solution is raised to 10 by adding aqueous sodium hydroxide, the solution is then extracted twice with ether,- which extract is washed with a saturated a Rr-CH-(il-Rz I H 4 and in which each of the radicals R and R stands for a member of the group consisting of 3-pyridyl and 4-pyridyl,

and each of the radicals R and R stands for lower alkyl,

and therapeutically acceptable acid addition salts thereof.

2. Compounds of the formula:

N N AH R4 in which each of the radicals R and R stands for lower alkyl.

3. Z-methyl-l,2-bis-(3-pyridyl)-propane-1-ol. 4. Compounds of the formula:

a N D iFH-OH R in. which each of radicals R and R stands for lower alkyl.

5. 3,3-bis-(3-pyridyl)-butane-2-ol. 6. Compounds of the formula:

in which each of the radicals R and R stands for lower alkyl.

7. Z-methyl-l,2-bis-(4-pyridyl)-propane-1-ol.

8. Compounds of the formula:

in which each of the radicals R and R stands for lower alkyl.

9. 3,3-bis-(4-pyridy1)-butane-2-ol. 10. In the process for the preparation of a member of the group consisting of compounds of the formulae:

lia R1CH-(|:lR9

H R4 and Ilia R1-CRg (DH-OH R4 in which each of the radicals R and R stands for a member of the group consisting of B-pyridyl and 4-pyridyl, and each of the radicals R and R stands for lower alkyl, and therapeutically acceptable acid addition salts thereof, the step which comprises treating a member of the group consisting of compounds of the formulae:

in which R R R and R have the above-given meaning and salts thereof, with a hydrogenating reagent selected from the group consisting of alkali metal aluminum hydrides and borohydrides.

11. Process according to claim 10, which comprises using lithium aluminum hydrides as a reducing reagent.

12. Process for the preparation of 2-methyl-l,2-bis-(3- pyridyl)-propane-l-ol which comprises treating Z-methyl- 1,2-bis'(3-pyridyl)-propane-l-one with lithium aluminum hydride.

References Cited in the file of this patent UNITED STATES PATENTS 2,756,237 Cislak July 24, 1956 2,759,946 Cislak et a1. Aug. 21, 1956 2,789,982. Cislak Apr. 23, 1957 2,794,807 Krapcho June 4, 1957 2,891,959 Cislak June 23, 1959 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: 